Aminoketone derivatives

ABSTRACT

Aminoketone derivatives according to the present invention strongly inhibit thiol protease such as calpain, papain, cathepsin B, cathepsin H, cathepsin L or the like and have excellent properties concerning absorbance on oral administration, tissue distribution and cell membrane permeability. The aminoketone derivatives cart thus be used as therapeutic agents for treating muscular dystrophy, cataract, cardiac infarction, stroke, Alzheimer&#39;s disease, amyotrophy, osteoporosis and hypercalcemia and so on. It may also be used as therapeutic agents for preventing metastasis of cancer. In addition, the present derivatives are also applicable as intermediates for the preparation of ketone derivatives, which have inhibitory activity against thiol protease.

FIELD OF THE INVENTION

This invention relates to novel aminoketone derivatives and, inparticular, to novel aminoketone derivatives and their pharmaceuticallyacceptable salts which strongly inhibit thiol protease such as papain,cathepsin B, cathepsin H, cathepsin L and calpain or the like.

BACKGROUND OF THE INVENTION

In accordance with the elucidation of the in vivo activity of thiolprotease such as papain, cathepsin B, cathepsin H, cathepsin L, calpainor the like, it has been found that their extraordinary hyperstheniacauses various diseases. Further, there are increasing reports whichshow thiol protease inhibitors are effective on such disease in animalmodels.

It is considered that thiol protease such as calpain, cathepsin B or thelike takes part in the initial process such as disappearance of Z linethrough the decomposition of muscular fiber protein in the collapse ofskeletal muscle as seen in muscular diseases such as muscular Dystrophy,amyotrophy or the like [Taisha (Metabolism), 25, extra-edition"Taisha-byo Highlight (Metabolic Diseases Highlight)", 183(1988)].Furthermore, E-64-d, namely a thiol protease inhibitor, has beenreported as having life-prolonging effect in experimental musculardystrophy hamster [Journal of Pharmacobio dynamics, 10, 678(1987)].Accordingly, such thiol protease inhibitors are expected to be useful astherapeutic agents for the treatment of muscular dystrophy, amyotrophyor the like.

The main cause of the post-ischemic cellular disorder which occursduring ischemic diseases such as cardiac infarction, stroke and the likeis active oxygen produced by xanthine oxidase. It has been reportedthat, during the ischemia, the increase in Ca²⁺ concentration results inthe activation of calpain which restrictively degrade xanthinedehydrogenase, a precursor of xanthine oxidase, to give xanthine oxidase[New England Journal of Medicine, 312, p.159, (1985)]. It has also beenreported that the activation of calpain may directly cause the necrosisof myocardial cells or neurocytes [Saishin Igaku, 43, p.783, (1988)].There have been reports that NCO-700, a calpain inhibitor, is effectiveon cardiac infarction when tested on animal models [ArzneimittelForschung/Drug Research, 36, p.190, p.671, (1986)], and that E-64-Cinhibits the degradation of microtubule-associated protein after thebrain ischemia [Brain Research, 526, p.177, (1990)]. These reportsindicate that a calpain inhibitor can be useful for the treatment ofischemic diseases such as cardiac infarction, stroke and the like.

The cause of senile plaque which is found specifically in the brain ofpatients suffering from Alzheimer's disease is known to be theprecipitated amyloid, a protein produced by the decomposition of anamyloid precursor protein (APP). Although APP does not give amyloid as anormal metabolite, it may be converted into amyloid under an abnormalmetabolism where protease is extremely activated, and precipitated assenile plaque [Scientific American, (11), p.40, (1991)]. Therefore,protease inhibitor is expected to be useful for the treatment ofAlzheimer's disease.

The activation of calpain has been observed in a brain trauma model ofrabbit [Neurochemical Research, 16, p.483, (1991)]. It has also beenobserved that the administration of leupeptin, a calpain inhibitor, canprotect axon in brain trauma models of rat [Journal of Neurosurgery, 65,p.92, (1986)]. Thus, calpain inhibitors are considered to be useful forimproving the consciousness disturbance or motor disturbance caused bybrain trauma.

It has also been reported that myelin-associated protein which exists indendrite of neurocytes is decomposed by calpain [Journal ofNeurochemistry, 47, p.1007, (1986)], indicating that calpain inhibitorsmay be effective on diseases caused by the demyelination of neurocytessuch as multiple sclerosis, peripheral nervous neuropathy and the like.

The main cause of the turbidity during cataract is hydrolytic productsof a water-soluble protein crystalline by protease in the lens. It hasbeen observed an increase in calcium concentration in lens ofcataractous animal models and some of human cataract [InvestigativeOphthalmology & Visual Science, 28, p.1702, (1987); Experimental EyeResearch, 34, p.413, (1982)]. The dominant protease contained in lens iscalpain [Lens and Eye Toxicity Research, 6, p.725, (1989)]. These factsindicate that the abnormal sthenia of calpain can be one of the causesof cataract. There is a report that E-64, an inhibitor of calpain, iseffective on cataract in animal models [Investigative Ophthalmology &Visual Science, 32, p.533, (1991)], indicating that calpain inhibitorscan be useful in the treatment of cataract.

Neutrophils, which are deeply associated with inflammation, show thedegranulation or production of superoxides in response to thestimulations by a chemotactic factor or phorbol ester through amechanism which appears to be mediated by protein kinase C (PKC).Calpain participates in the activation of PKC in the manner where itpromotes the degranulation and inhibits the production of superoxides[Journal of Biological Chemistry, 263, p.1915, (1988)]. In anotherreport, the concentration of cathepsin B in macrophage in rat is 30 to40 times that of leukocytes and neutrophils, and the concentration ofenzyme in inflammatory macrophage is 6 times that of normal macrophage[Journal of Biochemistry, 98, p.87, (1985)]. These facts indicate thatthiol protease inhibitors are useful as anti-inflammatory drugs.

The type I allergy reaction is mediated by immunoglobulin E (IgE)produced in a subject immunized with an antigen. Estatin A, a thiolprotease inhibitor, has been reported to specifically inhibit theproduction of IgE without affecting on the production of IgG [TheJournal of Antibiotics, 42, p.1362, (1989)]. Accordingly, thiol proteaseinhibitors are considered to be useful as antiallergic drugs.

In case of necrosis of hepatic cells, it is believed that impairment ofthe cell membrane leads to an increase in the permeability of Ca²⁺, anincrease in intracellular Ca²⁺ concentration, an activation of calpain,and, as the result, the decomposition of its substrate such as skeletalprotein takes place, which results in the death of cells. Accordingly, acalpain inhibitor can be used as a therapeutic agent for fulminanthepatitis.

Cathepsins such as cathepsin B and cathepsin L are involved indecomposition of bone collagen in osteoclast. It has been reported thatadministration of an inhibitor of cathepsins, E-64 or estatin A, to arat which has an enhanced bone destruction by administration ofparathyroid hormone leads to a decrease of calcium concentration andhydroxyproline concentration in blood [Biochemical and BiophysicalResearch Communication, 125, p.441, (1984): Japanese Patent Publication(kokai) No. 218610/1990]. Accordingly, it is believed that an inhibitorof cathepsins can be a therapeutic agent for osteoporosis, hypercalcemiaand the like.

There exist, as a substrate for calpain, sex hormone receptors such asestrogen receptor and androgen receptor, and it is known that calpainactivates these receptors. Accordingly, it is considered that anabnormal sthenia of calpain causes a disease which is suspected to becaused by an abnormal activation of the sex hormone receptors, forexample, breast carcinoma, prostatic carcinoma or prostatomegaly. It isbelieved that an inhibitor for calpain can be a therapeutic agent forthe above disease.

Receptors for epidermal growth factor (EGF) are also considered to beactivated in association with the canceration of cells. It is known thatcalpain activates the EGF receptors as its substrate. Furthermore, ithas been reported that calpain is activated in cells which have beeninfected with adult T cell human leukocyte virus (ATLV/HTLV-1)[Seikagaku, 57, p.1202, (1985)]. On the other hand, it is said thatcathepsin B is greatly involved in a process of cancer metastasisbecause it accelerates decomposition of collagen which is a importantstep for the cancer metastasis or directly decompose collagen, andbecause it has a profound correlation with plasma membrane of neoplasticcells [Tumor Progression and Markers, p.47, (1982); Journal ofBiological Chemistry, 256, p.8536, (1981)]. These facts suggest that athiol protease inhibitor has an ability to suppress the growth of cancercells and prevent the metastasis of cancer.

Activation of platelet causes the aggregation thereof which is a causeof thrombus. It has been reported that an inhibitor of calpain, E-64-d,suppressed aggregation of platelet caused by thrombin [ThrombosisResearch, 57, p.847, (1990)]. Accordingly, the inhibitor of calpain canbe used as an inhibitor against aggregation of platelet.

As described above, an abnormal sthenia of thiol protease causes variousdiseases and a validity of several thiol protease inhibitors in animalmodels has been reported. However, most of the known inhibitors, forexample, epoxy succinate derivatives such as E-64 [Agricultural andBiological Chemistry, 42, p.529, (1978)], E-64-d [Journal ofBiochemistry, 93, p.1305, (1983)], NCO-700 [Japanese Patent Publication(kokai) No. 126879/1983], and estatins A and B [The Journal ofAntibiotics, 42, p.1362, (1989)] or α-substituted ketone of a peptidesuch as chloromethyl ketone [Journal of Biochemistry, 99, p.173, (1986)]and acyloxymethyl ketone [Biochemistry, 30, p.4678, (1991)] areirreversible inhibitors. It is generally said that the irreversibleinhibitors are highly toxic because they are liable to react withnon-specifically with components constituting the living body, otherthan target enzymes. Therefore, there have been few compounds applicableto clinical use so far. Although peptidyl aldehydes such as leupeptin [The Journal of Antibiotics, 22, p.283, (1969)] or calpeptin [Journal ofEnzyme Inhibition, 3, p.195, (1990)] are known as reversible inhibitors,they also have problems in chemical and in vivo stabilities, cellmembrane permeabilities and the like.

SUMMARY OF THE INVENTION

The present inventors investigated into various compounds with the aimof developing reversible inhibitors against thiol protease, which haveexcellent properties in absorbance on oral administration, tissuedistribution and cell membrane permeability, and have found that certainderivatives of ketone have such desired properties.

More particularly, the subject matter of the present invention isdirected to an aminoketone derivative having the general formula (I) ora pharmaceutically acceptable salt thereof: ##STR1## wherein, R¹ ishydrogen, ##STR2## (R⁵ is selected from the group consisting of C₁ toC₂₀ alkyl optionally substituted by one or more substituents selectedfrom the group consisting of C₆ to C₁₄ aryl optionally substituted byone or more substituents, fluorenyl, a heterocyclic residue optionallysubstituted by one or more substituents, C₃ to C₁₅ cycloalkyl, C₃ to C₁₅cycloalkyloxy, C₆ to C₁₄ aryloxy optionally substituted by one or moresubstituents, C₇ to C₂₀ aralkyloxy optionally substituted by one or moresubstituents, C₆ to C₁₄ arylthio optionally substituted by one or moresubstituents, hydroxyl and C₂ to C₁₀ acyloxy; C₂ to C₁₀ alkenyloptionally substituted by C₆ to C₁₄ aryl optionally substituted by oneor more substituents or by a heterocyclic residue optionally substitutedby one or more substituents; C₆ to C₁₄ aryl optionally substituted byone or more substituents; and a heterocyclic residue optionallysubstituted by one or more substituents), R² and R⁴ are independentlyhydrogen or C₁ to C₅ alkyl, R³ is hydrogen, C₁ to C₂₀ alkyl optionallysubstituted by one or more substituents, or C₆ to C₁₄ aryl optionallysubstituted by one or more substituents, or when R³ and R⁴ are takentogether, they are C₁ to C₁₀ alkylene, --A-- is an oxygen atom, a sulfuratom or ##STR3## (R⁶ is hydrogen or C₁ to C₅ alkyl), n is an integer offrom 1 to 10, and X is a heterocyclic residue optionally substituted byone or more substituents.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is described in detail below. A compound accordingto the present invention is an aminoketone derivative having the generalformula (I) or a pharmaceutically acceptable salt thereof: ##STR4##wherein, R^(z) is hydrogen, ##STR5## (R⁵ is selected from the groupconsisting of C₁ to C₂₀ alkyl (methyl, decyl, icocyl, etc.) optionallysubstituted by one or more substituents selected from the groupconsisting of C₆ to C₁₄ aryl (phenyl, naphthyl, anthryl. etc.)optionally substituted by one or more substituents [one or moresubstituents selected from the group (hereinafter, referred to as "Group1") consisting of a halogen atom (a fluorine atom, a chlorine atom, abromine atom, an iodine atom, etc.), C₁ to C₅ alkyl (methyl, propyl,pentyl, etc.), trifluoromethyl, C₁ to C₅ alkoxy (methoxy, propoxy,pentyloxy, etc.), C₁ to C₅ cyclic acetal residue (methylenedioxy,propylenedioxy, amylenedioxy, etc.), hydroxyl group, C₂ to C₆ acyloxy(acetoxy, butyryloxy, valeryloxy, etc.), carboxyl, C₂ to C₆alkoxycarbonyl (methoxycarbonyl, propoxycarbonyl, pentyloxycarbonyl,etc.), oxo, C₂ to C₆ acyl (acetyl, butyryl, valeryl, etc.), amino, C₁ toC₅ monoalkylamino (methylamino, propylamino, pentylamino, etc.), C₂ toC₁₀ dialkylamino (dimethylamino, methylpropylamino, diisopropylamino,etc.), C₂ to C₆ acylamino (acetylamino, valerylamino, etc.), carbamoyl,C₂ to C₆ alkylcarbamoyl (methylcarbamoyl, propylcarbamoyl,pentylcarbamoyl, etc.), C₆ to C₁₄ aryl (phenyl, naphthyl, anthryl,etc.), C₆ to C₁₄ aryloxy (phenoxy, naphthyloxy, etc.) and C₆ to C₁₄arylamino (phenylamino, naphthylamino, etc.),] fluorenyl, a heterocyclicresidue [a heterocyclic residue (hereinafter, referred to as "Group 2")having a ring of 5 to 10 atoms including 1 to 4 hetero atoms selectedfrom the group consisting of oxygen atom, sulfur atom and nitrogen atom,e.g., furan, dihydrofuran, tetrahydrofuran, pyran, dihydropyran,tetrahydropyran, benzofuran, dihydrobenzofuran, isobenzofuran, chromene,chroman, isochroman, thiophene, benzothiophene, pyrrole, pyrroline,pyrrolidine, imidazole, imidazoline, imidazolidine, pyrazole,pyrazoline, pyrazolidine, triazole, tetrazole, pyridine, pyridineoxide,piperidine, pyrazine, piperazine, pyrimidine, pyridazine, indolizine,indole, indoline, isoindole, isoindoline, indazole, benzimidazole,purine, quinolizine, quinoline, phthalazine, naphtyridine, quinoxaline,quinazoline, cinnoline, pteridine, oxazole, oxazolidine, isooxazole,isoxazolidine, thiazole, thiazolidine, isothiazole, isothiazolidine,dioxane, dithian, morpholine, thiomorpholine) optionally substituted byone or more substituents (selected from the Group 1), C₃ to C₁₅cycloalkyl (cyclopropyl, cyclononyl, cyclopentadecyl, etc.), C₃ to C₁₅cycloalkyloxy (cyclopropyloxy, cyclononyloxy, pentadecyloxy, etc.), C₆to C₁₄ aryloxy (phenoxy, naphthyloxy, anthryloxy, etc.) optionallysubstituted by one or more substituents (selected from the Group 1), C₇to C₂₀ aralkyloxy (benzyloxy, phenylpentyloxy, naphthylmethoxy,naphthylethoxy, anthrylmethoxy, etc.) optionally substituted by one ormore substituents (selected from the Group 1), C₆ to C₁₄ arylthio(phenylthio, naphthylthio, anthrylthio, etc.) optionally substituted byone or more substituents (selected from the Group 1), hydroxyl and C₂ toC₁₀ acyloxy (acetylamino, valeryloxy, benzoyloxy, etc.); C₂ to C₁₀alkenyl (vinyl, hexenyl, decenyl, etc.) optionally substituted by C₆ toC.sub. 14 aryl (phenyl, naphthyl, anthryl) optionally substituted by oneor more substituents (selected from the Group 1) or by a heterocyclicresidue (Group 2) optionally substituted by one or more substituents(selected from the Group 1); C₆ to C₁₄ aryl (phenyl, naphthyl, anthryl,etc.) optionally substituted by one or more substituents (selected fromthe Group 1); and a heterocyclic residue (Group 2) optionallysubstituted by one or more substituents (selected from the Group 1)]; R²and R⁴ are independently hydrogen or C₁ to C₅ alkyl (methyl, propyl,pentyl, etc.); R³ is hydrogen, C₁ to C₂₀ alkyl (methyl, decyl, icocyl,etc.) optionally substituted by one or more substituents [selected fromthe group consisting of a halogen atom (a fluorine atom, a chlorineatom, a bromine atom, an iodine atom, etc.), C₃ to C₁₅ cycloalkyl(cyclopropyl, cyclononyl, cyclopentadecyl, etc.), hydroxyl group, C₁ toC₅ alkoxy (methoxy, propoxy, pentyloxy, etc.) optionally substituted bya heterocyclic residue (Group 2), C₆ to C₁₄ aryloxy (phenoxy,naphthyloxy, anthryloxy, etc.), C₇ to C₂₀ aralkyloxy (benzyloxy,phenylpentyloxy, naphthylmethoxy, naphthylethoxy, anthrylmethoxy, etc.),mercapto, C₁ to C₅ alkylthio (methylthio, propylthio, pentylthio, etc.)optionally substituted by a heterocyclic residue (Group 2), C₆ to C₁₄arylthio (phenylthio, naphthylthio, anthrylthio, etc.), C₇ to C₂₀aralkylthio (benzylthio, phenylethylthio, naphthylmethylthio,naphthylethylthio, etc.), carboxyl, carbamoyl, C₂ to C₆ alkoxycarbonyl(methoxycarbonyl, propoxycarbonyl, pentyloxycarbonyl, etc.), aheterocyclic residue (Group 2), amino, C₂ to C₅ monoalkylamino(methylamino, propylamino, pentylamino, etc.), C₂ to C₁₀ dialkylamino(dimethylamino, ethylmethylamino, dipentylamino, etc.), C₂ to C₆alkoxycarbonylamino (methoxycarbonylamino, propoxycarbonylamino,pentyloxycarbonylamino, etc.), C₂ to C₆ acylamino (acetylamino,valerylamino, etc.), guanidyl, oxo and C₆ to C₁₄ aryl (phenyl, naphthyl,anthryl, etc.)] or C₆ to C₁₄ aryl (phenyl, naphthyl, anthryl, etc.)optionally substituted by one or more substituents (selected from theGroup 1), or when R³ and R⁴ are taken together, they are C₁ to C₁₀alkylene (methylene, pentylene, octylene, etc.), --A-- is an oxygenatom, a sulfur atom or a group represented by ##STR6## R⁶ is hydrogen orC₁ to C₅ alkyl (methyl, propyl, pentyl, etc.)], n is an integer of from1 to 10, and X is a heterocyclic residue (Group 2) optionallysubstituted by one or more substituents (selected from the Group 1).

The aminoketone derivatives having the formula (I) according to thepresent invention are able to form salts. Specific examples of thesesalts are, in the presence of an acid group, metal salts such as alithium salt, a sodium salt, a potassium salt, a magnesium salt and acalcium salt or ammonium salts such as an ammonium salt, a methylammonium salt, a dimethyl ammonium salt, a trimethyl ammonium salt and adicyclohexyl ammonium salt and, in the presence of a base group, mineralacid salts such as hydrochloride, hydrobromide, sulfate, nitrate andphosphate or organic acid salts such as methane sulfonate, benzenesulfonate, paratoluene sulfonate, acetate, propionate, tartarate,fumatate, maleate, malate, oxalate, succinate, citrate, benzoate,mandelate, cinnamate and lactate.

The stereochemistry of the double bond of the aminoketone derivativeshaving the formula (I) is either one of E, Z and EZ. In addition, thestereochemical configuration of the asymmetric carbon is independentlyspecified by either one of R, S and RS.

Examples of the aminoketone derivatives having the formula (I) are setforth in Table 1 below.

                                      TABLE 1                                     __________________________________________________________________________    Comp.                                                                         No. R.sup.1              R.sup.2                                                                           R.sup.3       R.sup.4                                                                           A(CH.sub.2).sub.nX             __________________________________________________________________________         ##STR7##            H   H             H                                                                                  ##STR8##                      2                                                                                  ##STR9##            H   H             H                                                                                  ##STR10##                     3   H                    H   H             H                                                                                  ##STR11##                     4                                                                                  ##STR12##           H   H             H                                                                                  ##STR13##                     5                                                                                  ##STR14##           H   H             H                                                                                  ##STR15##                     6   H                    H   H             H                                                                                  ##STR16##                     7                                                                                  ##STR17##           H   H             H                                                                                  ##STR18##                     8                                                                                  ##STR19##           H   H             H                                                                                  ##STR20##                     9   H                    H   H             H                                                                                  ##STR21##                     10                                                                                 ##STR22##           H   H             H                                                                                  ##STR23##                     11                                                                                 ##STR24##           H   H             H                                                                                  ##STR25##                     12  H                    H   H             H                                                                                  ##STR26##                     13                                                                                 ##STR27##           H   H             H                                                                                  ##STR28##                     14                                                                                 ##STR29##           H   H             H                                                                                  ##STR30##                     15  H                    H   H             H                                                                                  ##STR31##                     16                                                                                 ##STR32##           H   H             H                                                                                  ##STR33##                     17                                                                                 ##STR34##           H   H             H                                                                                  ##STR35##                     18  H                    H   H             H                                                                                  ##STR36##                     19                                                                                 ##STR37##           H   H             H                                                                                  ##STR38##                     20                                                                                 ##STR39##           H   H             H                                                                                  ##STR40##                     21  H                    H   H             H                                                                                  ##STR41##                     22                                                                                 ##STR42##           H   CH.sub.3      H                                                                                  ##STR43##                     23                                                                                 ##STR44##           H   CH.sub.3      H                                                                                  ##STR45##                     24  H                    H   CH.sub.3      H                                                                                  ##STR46##                     25                                                                                 ##STR47##           H   CH.sub.3      H                                                                                  ##STR48##                     26                                                                                 ##STR49##           H   CH.sub.3      H                                                                                  ##STR50##                     27  H                    H   CH.sub.3      H                                                                                  ##STR51##                     28                                                                                 ##STR52##           H   CH.sub.3      CH.sub.3                                                                           ##STR53##                     29                                                                                 ##STR54##           H   CH.sub.3      CH.sub.3                                                                           ##STR55##                     30  H                    H   CH.sub.3      CH.sub.3                                                                           ##STR56##                     31                                                                                 ##STR57##           H   CH.sub.3      CH.sub.3                                                                           ##STR58##                     32                                                                                 ##STR59##           H   CH.sub.3      CH.sub.3                                                                           ##STR60##                     33  H                    H   CH.sub.3      CH.sub.3                                                                           ##STR61##                     34                                                                                 ##STR62##           H   CH.sub.3      CH.sub.3                                                                           ##STR63##                     35                                                                                 ##STR64##           H   CH.sub.3      CH.sub.3                                                                           ##STR65##                     36  H                    H   CH.sub.3      CH.sub.3                                                                           ##STR66##                     37                                                                                 ##STR67##           H   CH.sub.3      CH.sub. 3                                                                          ##STR68##                     38                                                                                 ##STR69##           H   CH.sub.3      CH.sub.3                                                                           ##STR70##                     39  H                    H   CH.sub.3      CH.sub.3                                                                           ##STR71##                     40                                                                                 ##STR72##           H   (CH.sub.3).sub.2 CH                                                                         H                                                                                  ##STR73##                     41                                                                                 ##STR74##           H   (CH.sub.3).sub.2 CH                                                                         H                                                                                  ##STR75##                     42  H                    H   (CH.sub.3).sub.2 CH                                                                         H                                                                                  ##STR76##                     43                                                                                 ##STR77##           H   (CH.sub.3).sub.2 CH                                                                         H                                                                                  ##STR78##                     44                                                                                 ##STR79##           H   (CH.sub.3).sub.2 CH                                                                         H                                                                                  ##STR80##                     45  H                    H   (CH.sub.3).sub.2 CH                                                                         H                                                                                  ##STR81##                     46                                                                                 ##STR82##           H   CH.sub.3 CH.sub.2 CH.sub.2                                                                  H                                                                                  ##STR83##                     47                                                                                 ##STR84##           H   CH.sub.3 CH.sub.2 CH.sub.2                                                                  H                                                                                  ##STR85##                     48  H                    H   CH.sub.3 CH.sub.2 CH.sub.2                                                                  H                                                                                  ##STR86##                     49                                                                                 ##STR87##           H   CH.sub.3 CH.sub.2 CH.sub.2                                                                  H                                                                                  ##STR88##                     50                                                                                 ##STR89##           H   CH.sub. 3 CH.sub.2 CH.sub.2                                                                 H                                                                                  ##STR90##                     51  H                    H   CH.sub.3 CH.sub.2 CH.sub.2                                                                  H                                                                                  ##STR91##                     52                                                                                 ##STR92##           H   (CH.sub.3).sub.2 CHCH.sub.2                                                                 H                                                                                  ##STR93##                     53                                                                                 ##STR94##           H   (CH.sub.3).sub.2 CHCH.sub.2                                                                 H                                                                                  ##STR95##                     54  H                    H   (CH.sub.3).sub.2 CHCH.sub.2                                                                 H                                                                                  ##STR96##                     55                                                                                 ##STR97##           H   (CH.sub.3).sub.2 CHCH.sub.2                                                                 H                                                                                  ##STR98##                     56                                                                                 ##STR99##           H   (CH.sub.3).sub.2 CHCH.sub.2                                                                 H                                                                                  ##STR100##                    57  H                    H   (CH.sub.3).sub.2 CHCH.sub.2                                                                 H                                                                                  ##STR101##                    58                                                                                 ##STR102##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR103##                    59                                                                                 ##STR104##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR105##                    60                                                                                 ##STR106##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR107##                    61  H                    H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR108##                    62                                                                                 ##STR109##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR110##                    63                                                                                 ##STR111##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR112##                    64                                                                                 ##STR113##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR114##                    65                                                                                 ##STR115##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR116##                    66                                                                                 ##STR117##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR118##                    67                                                                                 ##STR119##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR120##                    68                                                                                 ##STR121##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR122##                    69                                                                                 ##STR123##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR124##                    70                                                                                 ##STR125##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR126##                    71                                                                                 ##STR127##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR128##                    72                                                                                 ##STR129##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR130##                    73                                                                                 ##STR131##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR132##                    74                                                                                 ##STR133##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR134##                    75                                                                                 ##STR135##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR136##                    76                                                                                 ##STR137##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR138##                    77                                                                                 ##STR139##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR140##                    78  H                    H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR141##                    79                                                                                 ##STR142##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR143##                    80                                                                                 ##STR144##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR145##                    81  H                    H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR146##                    82                                                                                 ##STR147##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR148##                    83                                                                                 ##STR149##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR150##                    84  H                    H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR151##                    85                                                                                 ##STR152##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR153##                    86                                                                                 ##STR154##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR155##                    87                                                                                 ##STR156##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR157##                    88                                                                                 ##STR158##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR159##                    89                                                                                 ##STR160##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR161##                    90                                                                                 ##STR162##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR163##                    91                                                                                 ##STR164##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR165##                    92                                                                                 ##STR166##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR167##                    93                                                                                 ##STR168##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR169##                    94                                                                                 ##STR170##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR171##                    95                                                                                 ##STR172##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR173##                    96  H                    H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR174##                    97                                                                                 ##STR175##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR176##                    98                                                                                 ##STR177##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR178##                    99  H                    H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR179##                    100                                                                                ##STR180##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR181##                    101                                                                                ##STR182##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR183##                    102 H                    H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR184##                    103                                                                                ##STR185##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR186##                    104                                                                                ##STR187##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR188##                    105 H                    H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR189##                    106                                                                                ##STR190##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR191##                    107                                                                                ##STR192##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR193##                    108 H                    H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         H                                                                                  ##STR194##                    109                                                                                ##STR195##          H                                                                                  ##STR196##   H                                                                                  ##STR197##                    110                                                                                ##STR198##          H                                                                                  ##STR199##   H                                                                                  ##STR200##                    111 H                    H                                                                                  ##STR201##   H                                                                                  ##STR202##                    112                                                                                ##STR203##          H                                                                                  ##STR204##   H                                                                                  ##STR205##                    113                                                                                ##STR206##          H                                                                                  ##STR207##   H                                                                                  ##STR208##                    114 H                    H                                                                                  ##STR209##   H                                                                                  ##STR210##                    115                                                                                ##STR211##          H                                                                                  ##STR212##   H                                                                                  ##STR213##                    116                                                                                ##STR214##          H                                                                                  ##STR215##   H                                                                                  ##STR216##                    117 H                    H                                                                                  ##STR217##   H                                                                                  ##STR218##                    118                                                                                ##STR219##          H                                                                                  ##STR220##   H                                                                                  ##STR221##                    119                                                                                ##STR222##          H                                                                                  ##STR223##   H                                                                                  ##STR224##                    120 H                    H                                                                                  ##STR225##   H                                                                                  ##STR226##                    121                                                                                ##STR227##          H                                                                                  ##STR228##   H                                                                                  ##STR229##                    122                                                                                ##STR230##          H                                                                                  ##STR231##   H                                                                                  ##STR232##                    123 H                    H                                                                                  ##STR233##   H                                                                                  ##STR234##                    124                                                                                ##STR235##          H                                                                                  ##STR236##   H                                                                                  ##STR237##                    125                                                                                ##STR238##          H                                                                                  ##STR239##   H                                                                                  ##STR240##                    126 H                    H                                                                                  ##STR241##   H                                                                                  ##STR242##                    127                                                                                ##STR243##          H   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                              ##STR244##                    128                                                                                ##STR245##          H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                                              ##STR246##                    129 H                    H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                                              ##STR247##                    130                                                                                ##STR248##          H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                                     ##STR249##                    131                                                                                ##STR250##          H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                                     ##STR251##                    132 H                    H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                                     ##STR252##                    133                                                                                ##STR253##          H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                                     ##STR254##                    134                                                                                ##STR255##          H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                                     ##STR256##                    135 H                    H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                                     ##STR257##                    136                                                                                ##STR258##          H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                                     ##STR259##                    137                                                                                ##STR260##          H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                                     ##STR261##                    138 H                    H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                                     ##STR262##                    139                                                                                ##STR263##          H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                                     ##STR264##                    140                                                                                ##STR265##          H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                                     ##STR266##                    141 H                    H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                                     ##STR267##                    142                                                                                ##STR268##          H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                                     ##STR269##                    143                                                                                ##STR270##          H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                                     ##STR271##                    144 H                    H   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                                     ##STR272##                    145                                                                                ##STR273##          H                                                                                  ##STR274##   H                                                                                  ##STR275##                    146                                                                                ##STR276##          H                                                                                  ##STR277##   H                                                                                  ##STR278##                    147 H                    H                                                                                  ##STR279##   H                                                                                  ##STR280##                    148                                                                                ##STR281##          H                                                                                  ##STR282##   H                                                                                  ##STR283##                    149                                                                                ##STR284##          H                                                                                  ##STR285##   H                                                                                  ##STR286##                    150 H                    H                                                                                  ##STR287##   H                                                                                  ##STR288##                    151                                                                                ##STR289##          H                                                                                  ##STR290##   H                                                                                  ##STR291##                    152                                                                                ##STR292##          CH.sub.3                                                                           ##STR293##   H                                                                                  ##STR294##                    153                                                                                ##STR295##          H                                                                                  ##STR296##   H                                                                                  ##STR297##                    154                                                                                ##STR298##          H                                                                                  ##STR299##   H                                                                                  ##STR300##                    155                                                                                ##STR301##          H                                                                                  ##STR302##   H                                                                                  ##STR303##                    156                                                                                ##STR304##          CH.sub.3                                                                           ##STR305##   H                                                                                  ##STR306##                    157                                                                                ##STR307##          H                                                                                  ##STR308##   H                                                                                  ##STR309##                    158                                                                                ##STR310##          H                                                                                  ##STR311##   H                                                                                  ##STR312##                    159                                                                                ##STR313##          H                                                                                  ##STR314##   H                                                                                  ##STR315##                    160                                                                                ##STR316##          H                                                                                  ##STR317##   H                                                                                  ##STR318##                    161 H                    H                                                                                  ##STR319##   H                                                                                  ##STR320##                    162                                                                                ##STR321##          H                                                                                  ##STR322##   H                                                                                  ##STR323##                     ##STR324##

A method of preparing the compound according to the present invention isnow described. The aminoketone derivatives having the aforementionedformula (I) may be prepared through, but not limited to, the followingprocedures. ##STR325##

In the above formulae, R², R³, R⁴, n and X are as hereinabove definedwhile Boc is a tert-butoxycarbonyl group.

Chloromethyl ketone derivatives having the formula (II) can be readilysynthesized using a known method disclosed in Chemical andPharmaceutical Bulletin, vol. 37, page 3108, 1989. Thiomethyl ketonederivatives having the formula (III) can be produced by means ofdissolving such chloromethyl ketone derivatives in a solvent, e.g.,diethyl ether, tetrahydrofuran, dioxane, ethyl acetate, methylenechloride or chloroform, and reacting therewith mercaptan having theformula HS--(CH₂)_(n) --X in the presence of a base. The exemplifiedbase applicable includes sodium hydroxide, potassium hydroxide, sodiumhydride, triethylamine and pyridine. ##STR326##

In the above formulae, Boc, R², R³, R⁴, R⁶, n and X are as hereinabovedefined.

Diaminoketone derivatives having the formula (IV) can be produced bymeans of dissolving the chloromethyl ketone derivatives having theformula (II) in a solvent, e.g., diethyl ether, tetrahydrofuran,dioxane, ethyl acetate, chloroform or methylene chloride, and reactingtherewith amine having the formula: ##STR327##

In the above formulae, Boc, R², R³, R⁴, n and X are as hereinabovedefined.

Diazomethyl ketone having the formula (V) can be readily prepared usinga known method disclosed in Methods in Enzymology, vol. 80, page 802,1981. Oxymethyl ketone derivatives having the formula (VI) can beproduced by means of dissolving the diazomethyl ketone in a solvent suchas chloroform or methylene chloride and reacting therewith alcoholhaving the formula HO--(CH₂)_(n) --X in the presence of a transitionmetal catalyst including CuO, Rh₂ (OAc)₄ and so on. In this event, thecompound having the formula (V) may be dissolved directly in thealcohol, HO--(CH₂)_(n) --X, to advance the reaction without using thesolvent such as chloroform or methylene chloride. ##STR328##

In the above formulae, Boc, R², R³, R⁴, R⁵, A, n and X are ashereinabove defined.

The compound having the formula (VII), which is prepared according toany one of processes 1 through 3, has a Boc group. Deprotection of thisBoc group under the ordinary reaction conditions results in productionof amine having the formula (VIII) or a salt of the amine. Thedeprotection can be made with, but not limited to, a hydrochloric acidsolution, hydrochloric acid-ethanol, hydrogen chloride-ethyl acetate,hydrogen chloride-dioxane, hydrobromic acid and hydrogen bromide-aceticacid. In addition, the compound having the formula (IX) is produced bymeans of dissolving the compound (VIII) in an ordinary organic solventsuch as chloroform, methylene chloride, ethyl acetate anddimethylformamide and reacting therewith acylchloride having theformula: ##STR329## in the presence of amine such as triethylamine orpyridine. Likewise, the compound having the formula (X) is produced bymeans of reaction chloroformic derivatives having the formula:##STR330## with the compound having the formula (VIII).

It may become necessary to protect or deprotect functional groups ofeach compound produced during the sequence of operations in the abovementioned processes 1 through 4. Such protection or deprotection can beachieved readily with a common technique ordinarily used in organicsynthetic reactions.

For applying the compound according to the present invention to theclinical fields, the ratio of the therapeutically active componentrelative to the carrier can be altered within the range between 1% to99% by weight. For example, the compound according to the presentinvention may be formed into various dosage forms for oraladministration. Such dosage forms include granules, fine granules,powders, tablets, hard gelatin capsules, soft elastic capsules, syrup,emulsion, suspension and liquid preparation. Alternatively, the compoundmay be used as parenteral injections for intravenous, intramuscular orsubcutaneous injections. It may also be used as a suppository. Inaddition, the compound may be formed into powders for injection andprepared whenever it becomes necessary. The drug according to thepresent invention can be prepared with adequate organic or inorganicmedical diluent and/or solid or liquid carrier suitable for oral, rectalor parenteral administration. The vehicles, fillers, diluents andexcipient preferably used for solid preparation are: lactose, sucrose,starch, talc, cellulose, dextrin, kaolin and calcium carbonate. Theliquid preparation for oral administration, i.e., emulsion, syrup andsuspension include commonly used inactive diluent such as water andvegetable oil. The preparation may contain, other than the inactivediluent, auxiliaries such as moistening agents, suspending agents,sweetening agents, aromatic agents, coloring agents and preservatives.In addition, the preparation may be contained in, as the liquidpreparation, a capsule made of an absorbed material such as gelatin.Examples of the solvents and suspending agents preferably used forpreparing the preparation for the parenteral administration, i.e.,injection and suppository are: water, propylene glycol, polyethyleneglycol, benzyl alcohol, ethyl oleate and lecithin. Exemplified bases forthe suppository include cacao butter, emulsificated cacao butter, laurintallow and witepsol. The preparation can be made according to any one ofordinary methods.

The dosage relating to the present compound for oral administration toadults is generally in the range of between 0.01 to 1,000 mg as thedaily dose. It is, however, preferable to control the dosage dependingon the age, the degree of diseases and the symptom. The daily dose ofthe drug according to the present invention may be administered once aday. The same dose may also be administered two or three times a day atsuitable intervals or on alternate days or so.

The daily dose of 0.001 to 100 mg relating to the present compound forinjection to adults is preferably administered continuously orintermittently.

The aminoketone derivatives according to the present invention stronglyinhibits thiol protease such as calpain, papain, cathepsin B, cathepsinH and cathepsin L or the like and has excellent properties concerningabsorbance on oral administration, tissue distribution and cell membranepermeability. The aminoketone derivatives can thus be used astherapeutic agents for treating muscular dystrophy, cataract, cardiacinfarction, stroke, Alzheimer's disease, amyotrophy, osteoporosis andhypercalcemia. It may also be used as a therapeutic agent for preventingmetastasis of cancer. In addition, the present derivatives are alsoapplicable as the intermediates upon preparation of ketone derivatives,which has the inhibitory activity against thiol protease, as disclosedin Japanese Patent Application No. 165094/1992.

The foregoing features of the present invention will be more readilyapparent in the context of a specifically delineated set of examples anda reference. However, it should be understood that the present inventionis not limited to those particular examples and the reference as long asnot being depart from the spirit and scope of the appended claims.

EXAMPLE 1 Preparation of(S)-3-tert-butoxycarbonylamino-1-furfurylthio-2-heptanone (Compound No.58 in Table 1)

6.54 g of (S)-3-tert-butoxycarbonylamino-l-chloro-2-heptanone and 3.11 gof furfuryl mercaptan were dissolved in 200 ml of tetrahydrofuran, towhich 13 ml solution of 2N sodium hydroxide was added. The reactionsolution was stirred at a room temperature for 17 hours and a sodiumhydrogencarbonate solution was then added thereto. The solution wasextracted with ethyl acetate. The extracted solution was washed with asaturated sodium chloride solution and dried over magnesium sulfate,which was then filtered, concentrated and purified by the silica gelcolumn chromatography (eluent: 10% ethyl acetate containing hexane). Theobject of 7.82 g was obtained.

Yield: 92% IR(neat, cm⁻¹): 3353, 1705 NMR(CDCl₃, δ): 0.89(t, J=6.6 Hz,3H), 1.20-1.95(m, 6H), 1.44(s, 9H), 3.28(d, J=15 Hz, 1H), 3.39(d, J=15Hz, 1H), 3.74(s, 2H), 4.52(m, 1H), 5.09(m, 1H), 6.22(d, J=2.9 Hz, 1H),6.31(m, 1H), 7.36(m, 1H)

EXAMPLE 2 Preparation of (S)-3-amino-1-furfurylthio-2-heptanonehydrochloride (Compound No. 61 in Table 1)

7.8 g of (S)-3-tert-butoxycarbonylamino-1-furfurylthio-2-heptanoneobtained in Example 1 was dissolved in 80 ml of ethyl acetate, to which80 ml solution of 4N hydrogen chloride containing ethyl acetate wasadded. The reaction solution was stirred at a room temperature for 1hour. Subsequently, 100 ml of hexane was added to the latter. Crystalsgenerated were filtered and washed with hexane. The object of 5.93 g wasobtained.

Yield: 93% IR(KBr, cm⁻¹): 3350, 1730, 1590 NMR(DMSO-d₆, δ): 0.87(t,J=6.8 Hz, 3H), 1.16-1.40(m, 4H), 1.63-1.95(m, 2H), 3.55(d, J=16 Hz, 1H),3.70(d, J=16 Hz, 1H), 3.81(s, 2H), 4.27(m, 1H), 6.30(m, 1H), 6.41(m,1H), 7.61(m, 1H), 8.29(m, 3H)

EXAMPLE 3 Preparation of(S)-1-furfurylthio-3-phenoxyacetylamino-2-heptanone (Compound No. 66 inTable 1)

112 mg of (S)-3-amino-l-furfurylthio-2-heptanone hydrochloride obtainedin Example 2 and 82 mg of phenoxyacetyl chloride were dissolved in 2 mlof methylene chloride. 89 mg of triethylamine was added to the reactionsolution, which was then stirred at a room temperature for 3 hours. Asolution of 1N hydrochloric acid was added thereto, which was extractedwith methylene chloride. The extracted solution was successively washedwith water, a saturated sodium hydrogencarbonate solution and asaturated sodium chloride solution. It was dried over sodium sulfate andfiltered. The filtrate was concentrated and purified by the silica gelcolumn chromatography (eluent: 20% ethyl acetate containing hexane). Theobject of 149 mg was obtained.

Yield: 98% IR(KBr, cm⁻¹) 3450, 1715, 1670 NMR(CDCl₃, δ): 0.86(t, J=7.2Hz, 3H), 1.05-1.40(m, 2H), 1.43-1.75(m, 1H), 1.80-2.07(m, 1H), 3.27(d,J=15 Hz, 1H), 3.34(d, J=15 Hz, 1H), 3.72(s, 2H), 4.52(s, 2H), 4.90(m,1H), 6.21(d, J=2.5 Hz, 1H), 6.28(m, 1H), 6.90-7.58(m, 7H)

Similar operations were repeated to those made in Examples 1 through 3to prepare the following compound values of physical properties thereofare shown below.

EXAMPLE 4 preparation of1-tert-butoxycarbonylamino-3-furfurylthioacetone (Compound No. 1 inTable 1)

NMR(CDCl₃, δ): 1.45(s, 9H), 3.23(s, 2H), 3.73(s, 2H), 4.14(d, J=4.5 Hz,2H), 5.14(m, 1H), 6.23(m, 1H), 6.29(m, 1H), 7.39(m, 1H)

EXAMPLE 5 Preparation of3-tert-butoxycarbonylamino-1-furfurylthio-3-methyl-2-butanone (CompoundNo. 28 in Table 1)

NMR(CDCl₃, δ): 1.37-1.57(m, 15H), 3.49(s, 2H), 3.81(s, 2H), 5.05(br.s,1H), 6.23(d, J=2.9 Hz, 1H), 6.29(m, 1H), 7.35(m, 1H)

EXAMPLE 6 Preparation of 3-amino-1-furfurylthio-3-methyl-2-butanonehydrochloride (Compound No. 30 in Table 1)

IR(KBr, cm⁻¹): 3356, 1730, 1610 NMR(CD₃ OD, δ): 1.59(s, 6H), 3.59(s,2H), 3 83(s, 2H), 6.27(d, J=2.9 Hz, 1H), 6.34(m, 1H), 7.44(m, 1H)

EXAMPLE 7 Preparation of(S)-3-tert-butoxycarbonylamino-1-furfurylthio-4-methyl-2-pentanone(Compound No. 40 in Table 1)

NMR(CDCl₃, δ): 0.81(d, J=6.8 Hz, 3H), 1.00(d, J=6.8 Hz, 3H), 1.44(s,9H), 2.21(m, 1H), 3.28(d, J=15 Hz, 1H), 3.35(d, J=15 Hz, 1H), 3.75(s,2H), 4.48(m, 1H), 5.06(d, J=8.5 Hz, 1H), 6.22(d, J=2.9 Hz, 1H), 6.30(m,1H), 7.37(m, 1H)

EXAMPLE 8 Preparation of (S)-3-amino-1-furfurylthio-4-methyl-2-pentanonehydrochloride (Compound No. 42 in Table 1)

IR(KBr, cm⁻¹): 2966, 1730, 1589 NMR(CD₃ OD, δ): 0.96(d, J=7.0 Hz, 3H),1.18(d, J=7.0 Hz, 3H), 2.51(m, 1H), 3.39(d, J=15 Hz, 1H), 3.62(d, J=15Hz, 1H), 3.83(s, 2H), 4.38(m, 1H), 6.32(m, 1H), 6.40(m, 1H), 7.49(m, 1H)

EXAMPLE 9 Preparation of(S)-3-tert-butoxycarbonylamino-1-furfurylthio-2-hexanone (Compound No.46 in Table 1)

NMR(CDCl₃, δ): 0.89(t, J=7.1 Hz, 3H), 1.18-1.59(m, 3H), 1.41(s, 9H),1.76(m, 1H), 3.25(d, J=15 Hz, 1H), 3.30(d, J=15 Hz, 1H), 3.70(s, 2H),4.45(m, 1H), 5.03(d, J=7.6 Hz, 1H), 6.19(d, J=2.6 Hz, 1H), 6.26(m, 1H),7.32(m, 1H)

EXAMPLE 10 Preparation of (S)-3-amino-1-furfurylthio-2-hexanonehydrochloride (Compound No. 48 in Table 1)

IR(KBr, cm⁻¹): 2959, 1730, 1587 NMR(CDCl₃, δ): 0.98(t, J=7.2 Hz, 3H),1.42-1.77(m, 2H), 1.82-2.13(m, 2H), 3.37(d, J=14 Hz, 1H), 3.43(d, J=14Hz, 1H), 3.77(s, 2H), 4.59(dd, J=6.2 Hz, 5.2 Hz, 1H), 6.25-6.38(m, 2H),7.36(m, 1H), 8.69(s, 3H)

EXAMPLE 11 Preparation of(S)-3-[3-(2-acetylamino-4-thiazolyl)-2-propenoylamino]-1-furfurylthio-2-heptanone(Compound No. 71 in Table 1)

IR(neat, cm⁻¹): 3280, 1720, 1695, 1660, 1625 NMR(CDCl₃, δ): 0.83(t,J=6.8 Hz, 3H), 1.17-1.42(m, 4H), 1.59(m, 1H), 1.89(m, 1H), 2.22(s, 3H),3.35(d, J=15 Hz, 1H), 3.43(d, J=15 Hz, 1H), 3.74(s, 2H), 4.94(m, 1H),6.20(d, J=3.2 Hz, 1H), 6.28(m, 1H), 6.66(d, J=15 Hz, 1H), 6.76(d, J=7.8Hz, 1H), 7.02(s, 1H), 7.34(m, 1H), 7.49(d, J=15 Hz, 1H), 10.3(s, 1H)

EXAMPLE 12 Preparation of(S)-1-furfurylthio-3-[(2-phenylamino-4-thiazolyl)acetylamino]-2-heptanone(Compound No. 75 in Table 1)

IR(neat, cm⁻¹): 3300, 1720, 1705, 1660, 1600 NMR(CDCl₃, δ): 0.82(t,J=6.9 Hz, 3H), 1.12-1.38(m, 4H), 1.58(m, 1H), 1.85(m, 1H), 3.24(d, J=15Hz, 1H), 3.34(d, J=15 Hz, 1H), 3.59(s, 2H), 3.69(s, 2H), 4.75(m, 1H),6.19(d, J=2.8 Hz, 1H), 6.27(m, 1H), 6.39(s, 1H), 7.06(m, 1H),7.21-7.41(m, 6H), 7.52(d, J=7.7 Hz, 1H)

EXAMPLE 13 Preparation of(S)-3-tert-butoxycarbonylamino-1-(3-furylmethylthio)-2-heptanone(Compound No. 76 in Table 1)

NMR(CDCl₃, δ): 0.90(d, J=6.2 Hz, 3BE), 1.13-1.60(m, 5H), 1.47(s, 9H),1.81(m, 1H), 3.20(d, J=15 Hz, 1H), 3.29(d, J=15 Hz, 1H), 3.55(s, 2H),4.49(m, 1H), 5.05(d, J=5.8 Hz, 1H), 6.39(d, J=1.2 Hz, 1H), 7.35-7.42(m,2H)

EXAMPLE 14 Preparation of(S)-3-benzyloxycarbonylamino-1-furfurylthio-5-methyl-2-hexanone(Compound No. 53 in Table 1)

IR(neat, cm⁻¹): 3350, 1720, 1700, 1620 NMR(CDCl₃,δ): 0.88-1.02(m, 6H),1.42(m, 1H), 1.55-1.80(m, 2H), 3.29(d, J=8.5 Hz, 1H), 3.35(d, J=8.5 Hz,1H), 3.73(s, 2H), 4.61(m, 1H), 5.11(s, 2H), 5.20(d, J=8.2 Hz, 1H),6.21(m, 1H), 6.28(m, 1H), 7.26-7.40(m, 6H)

EXAMPLE 15 Preparation of(S)-3-tert-butoxycarbonylamino-1-(3-thienylmethylthio)-2-heptanone(Compound No. 82 in Table 1)

Melting Point: 43°-45° C. IR(KBr, cm⁻¹): 3383, 1705, 1686, 1510NMR(CDCl₃, δ): 0.89(t, J=6.7 Hz, 3H), 1.18-1.40(m, 4H), 1.45(s, 9H),1.52(m, 1H), 1.80(m, 1H), 3.17(d, J=14.8 Hz, 1H), 3.27(d, J=14.8 Hz,1H), 3.73(s, 2H), 4.49(m, 1H), 5.05(br.d, J=7.6 Hz, 1H), 7.06(d, J=5.0Hz, 1H), 7.16(br.s, 1H), 7.29(m, 1H)

EXAMPLE 16 Preparation of(S)-3-amino-1-(3-thienylmethylthio)-2-heptanone hydrochloride (CompoundNo. 84 in Table 1)

Melting Point: 91°-94° C. IR(KBr, cm⁻¹): 1730, 1588, 1505 NMR(CD₃ OD,δ): 0.95(t, J=6.8 Hz, 3H), 1.20-1.44(m, 4H), 1.78(m, 1H), 1.96(m, 1H),3.30(d, J=].4.9 Hz, 1H), 3.49(d, J=14.9 Hz, 1H), 3.79(s, 2H), 4.34(dd,J=7.8 Hz, 4.3 Hz, 1H), 7.09(dd, J=5.0 Hz, 1.3 Hz, 1H), 7.26(dd, J=2.1Hz, 1.3 Hz, 1H), 7.39(dd, J=5.0 Hz, 3.0 Hz, 1H)

EXAMPLE 17 Preparation of(S)-3-phenoxyacetylamino-1-(3-thienylmethylthio)-2-heptanone (CompoundNo. 86 in Table 1)

IR(neat, cm⁻¹): 3406, 1678, 1522 NMR(CDCl₃, δ): 0.87(t, J=6.7 Hz, 3H),1.10-1.40(m, 4H), 1.52(m, 1H), 1.90(m, 1H), 3.16(d, J=14.6 Hz, 1H),3.25(d, J=14.6 Hz, 1H), 3.72(s, 2H), 4.53(s, 2H), 4.93(m, 1H), 6.96(d,J=8.5 Hz, 2H), 7.01(m, 1H), 7.05(d, J=6.5 Hz, 1H), 7.16(br.s, 1H),7.30(m, 1H), 7.37(m, 2H)

EXAMPLE 18 Preparation of(S)-3-(3-methoxyphenoxyacetylamino)-1-(3-thienylmethylthio)-2-heptanone(Compound No. 87 in Table 1)

IR(neat, cm⁻¹): 3407, 1678, 1603, 1522 NMR(CDCl₃, δ): 0.86(t, J=6.8 Hz,3H), 1.10-1.40(m, 4H), 1.60(m, 1H), 1.90(m, 1H), 3.16(d, J=14.7 Hz, 1H),3.25(d, J=14.7 Hz, 1H), 3.72(s, 2H), 3.81(s, 3H), 4.51(d, J=1.2 Hz, 2H),4.92(m, 1H), 6.52(d, J=1.4 Hz, 1H), 6.53-6.61(m, 2H), 7.05(dd, J=5.0 Hz,1.3 Hz, 1H), 7.11(br.d, J=7.9 Hz, 1H), 7.15(d, J=1.1 Hz, 1H), 7.22(ddd,J=8.4 Hz, 8.4 Hz, 1.0 Hz, 1H), 7.28(dd, 5.0 Hz, 3.0 Hz, 1H)

EXAMPLE 19 Preparation of(S)-3-acetoxyacetylamino-1-(3-thienylmethylthio)- 2-heptanone (CompoundNo. 89 in Table 1)

IR(neat, c⁻¹): 3310, 1.752, 1674, 1530 NMR(CDCl₃, δ): 0.89(t, J=6.7 Hz,3H), 1.15-1.40(m, 4H), 1.60(m, 1H), 1.90(m, 1H), 2.21(s, 3H), 3.17(d,J=14.7 Hz, 1H), 3.26(d, J=14.7 Hz, 1H), 3.73(s, 2H), 4.59(s, 2H),4.91(m, 1H), 6.72(br.d, J=6.7 Hz, 1H), 7.06(d, J=4.9 Hz, 1H), 7.16(br.s,1H), 7.29(dd, J=4.9 Hz, 3.1 Hz, 1H)

EXAMPLE 20 Preparation of(S)-3-(3-phenoxybenzoylamino)-1-(3-thienylmethylthio)-2-heptanone(Compound No. 93 in Table 1)

IR(neat, cm⁻¹): 3320, 1711, 1645, 1579, 1531 NMR(CDCl₃, δ): 0.88(t,J=6.8 Hz, 3H), 1.15-1.40(m, 4H), 1.64(m, 1H), 2.00(m, 1H), 3.22(d,J=14.7 Hz, 1H), 3.31(d, J=14.7 Hz, 1H), 3.74(s, 2H), 5.03(m, 1H),6.71(br.d, J=7 Hz, 1H), 7.02-7.06(m, 3H), 7.13-7.16(m, 3H), 7.30-7.42(m,4H), 7.47-7.51(m, 3H)

EXAMPLE 21 Preparation of(S)-3-tert-butoxycarbonylamino-4-cyclohexyl-1-furfurylthio-2-butanone(Compound No. 109 in Table 1)

NMR(CDCl₃, δ): 0.80-1.08(m, 2H), 1.12-1.53(m, 6H), 1.45(s, 9H),1.55-1.78(m, 4H), 1.80-1.95(m, 1H), 3.30(d, J=11 Hz, 1H), 3.38(d, J=11Hz, 1H), 3.74(s, 2H), 4.54(m, 1H), 5.92(d, J=7.1 Hz, 1H), 6.23(m, 1H),6.30(m, 1H), 7.36(m, 1H)

EXAMPLE 22 Preparation of(S)-4-tert-butoxycarbonylamino-6-furfurylthio-5-oxohexanoic acid methylester (Compound No. 115 in Table 1)

NMR(CDCl₃ δ): 1.40(s, 9H), 1.63-1.85(m, 2H), 2.05-2.42(m, 2H), 3.27(d,J=15 Hz, 1H), 3.35(d, J=15 Hz, 1H), 3.64(s, 3H), 3.69(s, 2H), 4.52(m,1H), 5.19(d, J=5.7 Hz, 1H), 6.19(d, J=3.2 Hz, 1H), 6.27(m, 1H), 7.35(m,1H)

EXAMPLE 23 Preparation of1-tert-butoxycarbonylamino-1-(3-pyridylmethylthioacetyl) cyclohexane(Compound No. 130 in Table 1)

NMR(CDCl₃, δ): 1.31-1.58(m, 10H), 1.58-1.73(m, 7H), 1.83-2.11(m, 2H),3.41(s, 2H), 3.79(s, 2H), 5.52(s, 1H), 7.24(m, 1H), 7.73(ddd, J=8.1 Hz,1.8 Hz, 1.8 Hz, 1H), 8.48(m, 1H), 8.57(s, 1H)

EXAMPLE 24 Preparation of 1-amino-1-(3-pyridylmethylthioacetyl)cyclohexane hydrochloride (Compound No. 132 in Table 1)

NMR(CD₃ OD, δ): 1.37-1.72(m, 4H), 1.72-1.92(m, 4H), 2.04-2.22(m, 2H),3.75(s, 2H), 4.08(s, 2H), 8.11(dd, J=8.1 Hz, 5.9 Hz, 1H), 8.73(d, J=8.1Hz, 1H), 8.81(d, J=5.9 Hz, 1H), 8.96(s, 1H)

EXAMPLE 25 Preparation of(S)-3-tert-butoxycarbonylamino-1-furfurylthio-4-phenyl-2-butanone(Compound No. 151 in Table 1)

NMR(CDCl₃, δ): 1.41(s, 9H), 2.90-3.15(m, 2H), 3.17(d, J=14 Hz, 1H),3.26(d, J=14 Hz, 1H), 3.65(s, 2H), 4.73(dt, J=6.8 Hz, 6.6 Hz, 1H),5.06(d, J=6.8 Hz, 1H), 6.18(d, J=3.2 Hz, 1H), 6.29(dd, J=3.2 Hz, 1.9 Hz,1H), 7.10-7.22(m, 2H), 7.22-7.38(m, 4H)

EXAMPLE 26 Preparation of (S)-3-amino-1-furfurylthio-4-phenyl-2-butanonehydrochloride (Compound No. 161 in Table 1)

NMR (DMSO-d₆, δ): 3.02-3.23(m, 2H), 3.36(d, J=16 Hz, 1H), 3.59(d, J=16Hz, 1H), 3.69(d, J=14 Hz, 1H), 3.87(d, J=14 Hz, 1H), 4.54(m, 1H),6.24(d, J=3.1 Hz, 1H), 6.38(dd, J=3.1 Hz, 1.9 Hz, 1H), 7.20-7.40(m, 5H),7.57(d, J=1.9 Hz, 1H), 8.47(s, 3H)

EXAMPLE 27 Preparation of(S)-3-(N-tert-butoxycarbonyl-N-methylamino)-1-furfurylthio-4-phenyl-2-butanone(Compound No. 152 in Table 1)

NMR(CDCl₃, δ): 1.35(s, 5.4H), 1.40(s, 3.6H), 2.57(s, 1.2H), 2.62(s,1.8H), 2.80-3.05(m, 1H), 3.12-3.43(m, 3H), 3.66(s, 0.8H), 3.67(s, 1.2H),4.60-4.82(m, 1H), 6.20(d, J=2.8 Hz, 1H), 6.31(m, 1H), 7.10-7.43(m, 6H)

EXAMPLE 28 preparation of(S)-1-furfurylthio-3-isobutoxycarbonylamino-4-phenyl-2-butanone(Compound No. 153 in Table 1)

Melting Point: 58°-59° C. IR(KBr, cm⁻¹): 3330, 1725, 1683 NMR(CDCl₃, δ):0.90(d, J=6.7 Hz, 6H), 1.88(m, 1H), 2.95-3.15(m, 2H), 3.18(s, 2H),3.64(s, 2H), 3.83(d, J=6.7 Hz, 2H), 4.78(m, 1H), 5.21(d, J=7.2 Hz, 1H),6.18(d, J=3.3 Hz, 1H), 6.29(dd, J=3.3 Hz, 1.9 Hz, 1H), 7.10-7.18(m, 2H),7.18-7.38(m, 4H)

EXAMPLE 29 Preparation of(S)-3-benzyloxycarbonylamino-1-furfurylthio-4-phenyl-2-butanone(Compound No. 155 in Table 1)

Melting Point: 64°-6620 C. IR(KBr, cm⁻¹): 3320, 1730, 1640 NMR(CDCl₃,δ): 2.95-3.25(m, 2H), 3.17(s, 2H), 3.63(s, 2H), 4.84(d, J=7.5 Hz, 1H),5.08(s, 2H), 5.33(d, J=7.5 Hz 1H), 6.17(m, 1H), 6.27(m, 1H),7.10-7.45(m, 11H)

EXAMPLE 30 Preparation of(S)-3-fluorenylmethoxycarbonylamino-1-furfurylthio-4-phenyl-2-butanone(Compound No. 159 in Table 1)

NMR(CDCl₃, δ): 2.95-3.10(m, 2H), 3.15<s, 2H), 3.64(s, 2H), 4.19(t, J=6.7Hz, 1H), 4.30-4.50(m, 2H), 4.84(q, J=7.5 Hz, 1H), 5.31(d, J=7.5 Hz, 1H),6.17(m, 1H), 6.27(m, 1H), 7.10-7.16(m, 2H), 7.20-7.45(m, 8H),7.50-7.60(m, 2H), 7.75-7.79(m, 2H)

EXAMPLE 31 Preparation of(S)-3-(2,5-dioxo-1-pyrrolidyloxycarbonylamino)-1-furfurylthio-4-phenyl-2-butanone(Compound No. 160 in Table 1)

NMR(CDCl₃, δ): 3.04(m, 2H), 3.17(s, 2H), 3.65(s, 4H), 3.68(s, 2H),4.83(q, J=7.3 Hz, 1H), 5.21(d, J=7.3 Hz, 1H), 6.18(m, 1H), 6.29(m, 1H),7.14-7.35(m, 6H)

EXAMPLE 32 Preparation of(S)-1-furfurylthio-3-isovalerylamino-4-phenyl-2-butanone (Compound No.163 in Table 1)

Melting Point: 94°-95° C. IR(KBr, cm⁻¹): 3320, 1712, 1643 NMR(CDCl₃, δ):0.87(d, J=6.2 Hz, 3H), 0.89(d, J=5.6 Hz, 3H), 1.53(m, 1H), 2.03(m, 2H)2.95-3.20(m, 2H), 3.19(s, 2H), 3.65(s, 2H), 5.07(dt, J=7.2 Hz, 6.5 Hz,1H), 5.91(d, J=7.2 Hz, 1H), 6.18(d, J=3.1 Hz, 1H), 6.29(dd, J=3.1 Hz,2.0 Hz, 1H), 7.05-7.38(m, 6H)

EXAMPLE 33 Preparation of(S)-1-furfurylthio-3-isohexanoylamino-4-phenyl-2-butanone (Compound No.164 in Table 1)

Melting Point: 68°-71° C. IR(KBr, cm⁻¹): 3320, 1710, 1640 NMR(CDCl₃, δ):0.87(d, J=4.5 Hz, 6H), 1.40-1.60(m, 3H), 2.17(t, J=7.8 Hz, 2H),2.95-3.20(m, 2H), 3.20(s, 2H), 3.66(s, 2H), 5.05(q, J=7.2 Hz, 1H),5.93(d, J=7.2 Hz, 1H), 6.19(m, 1H), 6.29(m, 1H), 7.12-7.40(m, 6H)

EXAMPLE 34 Preparation of(S)-1-furfurylthio-4-phenyl-3-(3-phenylpropyonylamino)-2-butanone(Compound No. 166)

NMR(CDCl₃, δ): 2.48(m, 2H), 2.92(t, J=7.6 Hz, 2H), 3.01(m, 2H), 3.12(s,2H), 3.61(s, 2H), 5.03(q, J=7.2 Hz, 1H), 5.89(d, J=7.2 Hz, 1H), 6.16(m,1H), 6.28(m, 1H), 7.01-7.06(m, 2H), 7.15-7.35(m, 9H)

EXAMPLE 35 Preparation of(S)-1-furfurylthio-3-(1-naphtylacetylamino)-4-phenyl-2-butanone(Compound No. 168 in Table 1)

NMR(CDCl₃, δ): 2.75-2.95(m, 2H), 3.07(s, 2H), 3.51(s, 2H), 3.99(s, 2H),4.90(q, J=7.5 Hz, 1H), 5.79(d, J=7.5 Hz, 1H), 6.11(m, 1H), 6.26(m, 1H),6.65-6.72(m, 2H), 6.96-7.10(m, 3H), 7.20-7.35(m, 3H), 7.40-7.55(m, 2H),7.80-7.92(m, 2H)

EXAMPLE 36 Preparation of(S)-1-furfurylthio-3-(2-naphtylacetylamino)-4-phenyl-2-butanone(Compound No. 169 in Table 1)

NMR(CDCl₃, δ): 2.87(dd, J=14 Hz, 7.1 Hz, 1H), 3.01(dd, J=14 Hz, 7.1 Hz,1H), 3.18(s, 2H), 3.61(s, 2H), 3.69(s, 2H), 4.96(q, J=7.0 Hz, 1H),5.88(d, J=7.0 Hz, 1H), 6.15(m, 1H), 6.27(m, 1H), 6.84-6.89(m, 2H),7.0-7.12(m, 3H), 7.23(m, 1H), 7.32(m, 1H), 7.49-7.53(m, 2H), 7.62(s,1H), 7.76-7.87(m, 3H)

EXAMPLE 37 Preparation of(S)-3-cyclohexyloxyacetylamino-1-furfurylthio-4-phenyl-2-butanone(Compound No. 170 in Table 1)

IR (neat, cm⁻¹): 3410, 1710, 1670 NMR(CDCl₃, δ): 1.16-1.40(m, 5H),1.45-1.85(m, 5H), 3.10(m, 2H), 3.19(s, 2H), 3.21(m, 1H), 3.64(s, 2H),3.92(s, 2H) 5.04(q, J=7.0 Hz, 1H), 6.19(m, 1H), 6.29(m, 1H),7.12-7.36(m, 7H)

EXAMPLE 38 Preparation of(S)-1-furfurylthio-3-phenoxyacetylamino-4-phenyl-2-butanone (CompoundNo. 171 in Table 1)

IR(KBr, cm⁻¹): 3350, 1700, 1655 NMR(CDCl₃, δ): 3.0-3.16(m, 2H), 3.16(s,2H), 3.63(s, 2H) 4.47(s, 2H), 5.14(q, J=7.2 Hz, 1H), 6.17(m, 1H),6.28(m, 1H), 6.85-6.90(m, 2H), 7.03(t, J=7.0 Hz, 1H), 7.10-7.16(m, 2H),7.20-7.38(m, 6H)

EXAMPLE 39 Preparation of(S)-3-(2-chlorophenoxyacetylamino)-1-furfurylthio-4-phenyl-2-butanone(Compound No. 172 in Table 1)

NMR(CDCl₃, δ): 3.11(m, 2H), 3.20(s, 2H), 3.66(s, 2H), 4.46(d, J=14 Hz,1H), 4.54(d, J=14 Hz, 1H), 5.13(q, J=7.2 Hz, 1H), 6.19(m, 1H), 6.28(m,1H), 6.84(d, J=8.1 Hz, 1H), 6.99(m, 1H), 7.16-7.42(m, 9H)

EXAMPLE 40 preparation of(S)-3-(4-chlorophenoxyacetylamino)-1-furfurylthio-4-phenyl-2-butanone(Compound No. 174 in Table 1)

Melting Point: 95°-98° C. IR(KBr, cm⁻¹): 3280, 1730, 1670 NMR(CDCl₃, δ):3.08(m, 2H), 3.17(s, 2H), 3.63(s, 2H) 4.44(s, 2H), 5.14(q, J=7.0 Hz,1H), 6.18(m, 1H), 6.29(m, 1H), 6.75-6.82(m, 2H), 7.02-7.36(m, 9H)

EXAMPLE 41 Preparation of(S)-1-furfurylthio-3-(3-methylphenoxyacetylamino)-4-phenyl-2-butanone(Compound No. 176 in Table 1)

Melting Point: 76°-78° C. IR(KBr, cm⁻¹): 3279, 1730, 1669, 1609NMR(CDCl₃, δ): 2.34(s, 3H), 3.0-3.17(m, 2H), 3.15(s, 2H), 3.62(s, 2H),4.46(s, 2H), 5.13(dt, J=7.6 Hz, 6.9 Hz, 1H), 6.18(d, J=3.1 Hz, 1H),6.28(dd, J=3.1 Hz, 1.9 Hz, 1H), 6.60-6.73(m, 2H), 6.85(d, J=7.9 Hz, 1H),7.05-7.37(m, 8H)

EXAMPLE 42 Preparation of(S)-1-furfurylthio-4-phenyl-3-(3-trifluoromethylphenoxyacetylamino)-2-butanone(Compound No. 179 in Table 1)

Melting Point: 72°-80° C. IR(KBr, cm⁻¹): 3414, 1711, 1684 NMR(CDCl₃, δ):3.02-3.23(m, 2H), 3.17(s, 2H), 3.64(s, 2H), 4.47(d, J=15 Hz, 1H),4.54(d, J=15 Hz, 1H), 5.15(dt, J=7.5 Hz, 6.8 Hz, 1H), 6.19(d, J=3.1 Hz,1H), 6.29(dd, J=3.1 Hz, 1.9 Hz, 1H), 6.98-7.53(m, 11H)

EXAMPLE 43 Preparation of(S)-1-furfurylthio-3-(3-methoxyphenoxyacetylamino)-4-phenyl-2-butanone(Compound No. 182 in Table 1)

IR(KBr, cm⁻¹) 3281, 1730, 1671, 1603 NMR(CDCl₃, δ): 3.0-3.23(m, 2H),3.15(s, 2H), 3.62(s, 2H), 3.80(s, 3H), 4.46(s, 2H), 5.13(dt, J=7.7 Hz,6.8 Hz, 1H), 6.17(d, J=3.2 Hz, 1H), 6.28(dd, J=3.2 Hz, 2.0 Hz, 1H),6.35-6.52(m, 2H), 6.50-6.63(m, 1H), 7.0-7.40(m, 8H)

EXAMPLE 44 Preparation of(S)-1-furfurylthio-3-(2-methoxyphenoxyacetylamino)-4-phenyl-2-butanone(Compound No. 181 in Table 1)

NMR(CDCl₃, δ): 2.96-3.20(m, 2H), 3.15(s, 2H), 3.61(s, 2H), 3.84(s, 3H),4.53(s, 2H), 5.12(q, J=7.5 Hz, 1H), 6.16(m, 1H), 6.27(m, 1H),6.83-7.36(m, 10H), 7.65(d, J=7.5 Hz, 1H)

EXAMPLE 45 Preparation of(S)-1-furfurylthio-3-(2-phenoxypropyonylamino)-4-phenyl-2-butanone(Compound No. 184 in Table 1)

NMR(CDCl₃, δ): 1.43(d, J=6.3 Hz, 1.5H), 1.54(d, J=6.23 Hz, 1.5H),2.95-3.20(m, 4H), 3.50(s, 1H), 3.65(s, 1H), 4.64(m, 1H), 5.02(m, 1H),6.12(m, 0.5H), 6.20(m, 0.5H), 6.25(m, 0.5H), 6.29(m, 0.5H), 6.79-7.04(m,5H), 7.08-7.40(m, 7H)

EXAMPLE 46 Preparation of(S)-1-furfurylthio-3-(2-phenoxybutyrylamino)-4-phenyl-2-butanone(Compound No. 185 in Table 1)

NMR(CDCl₃, δ): 0.89(t, J=7.3 Hz, 1.5H), 1.01(t, J=7.3 Hz, 1.5H),1.50-2.0(m, 2H), 2.99(s, 1H), 3.19(s, 1H), 2.92-3.20(m, 2H), 3.48(s,1H), 3.64(s, 1H), 4.47(m, 1H), 5.04(q, J=7.3 Hz, 1H), 6.10(m, 0.5H),6.19(m, 0.5H), 6.26(m, 0.5H), 6.30(m, 0.5H), 6.78-7.04(m, 5H),7.10-7.36(m, 7H)

EXAMPLE 47 Preparation of(S)-3-benzyloxyacetylamino-1-furfurylthio-4-phenyl-2-butanone (CompoundNo. 186 in Table 1)

NMR(CDCl₃, δ): 2.95-3.20(m, 2H), 3.18(s, 2H), 3.64(s, 2H), 3.90(d, J=15Hz, 1H), 3.99(d, J=15 Hz, 1H), 4.46(d, J=14 Hz, 1H), 4.55(d, J=14 Hz,1H), 5.06(q, J=7.3 Hz, 1H), 6.18(d, J=2.9 Hz, 1H), 6.28(m, 1H),7.0-7.45(m, 12H)

EXAMPLE 48 Preparation of(S)-1-furfurylthio-3-(1-naphtoxyacetylamino)-4-phenyl-2-butanone(Compound No. 188 in Table 1)

Melting Point: 104°-106° C. IR(KBr, cm³¹ 1): 3310, 1710, 1665 NMR(CDCl₃,δ): 3.12(m, 2H), 3.22(s, 2H), 3.65(s, 2H), 4.62(d, J=13 Hz, 1H), 4.71(d,J=13 Hz, 1H), 5.18(q, J=7.5 Hz, 1H), 6.18(m, 1H), 6.28(m, 1H), 6.74(d,J=7.3 Hz, 1H), 7.05-7.36(m, 8H), 7.48-7.60(m, 3H), 7.84(m, 1H), 8.05(m,1H)

EXAMPLE 49 Preparation of(S)-1-furfurylthio-3-(2-naphtoxyacetylamino)-4-phenyl-2-butanone(Compound No. 189 in Table 1)

Melting Point: 115°-118° C. IR(KBr, cm⁻¹): 3300, 1730, 1670 NMR(CDCl₃,δ): 3.05-3.18(m, 2H), 3.16(s, 2H), 3.60(s, 2H), 4.60(s, 2H), 5.15(q,J=7.5 Hz, 1H), 6.16(m, 1H), 6.27(m, 1H), 7.05-7.20(m, 10H), 7.35-7.50(m,2H), 7.70-7.82(m, 1H)

EXAMPLE 50 Preparation of(S)-1-furfurylthio-4-phenyl-3-phenylthioacetylamino-2-butanone (CompoundNo. 190 in Table 1)

IR(KBr, cm⁻¹): 3460 , 3300 , 1730 , 1670 NMR(CDCl₃, δ): 2.99(m, 2H),3.05(s, 2H), 3.57(s, 2H), 3.60(s, 2H), 4.99(q, J=7.0 Hz, 1H), 6.15(m,1H), 6.28(m, 1H), 7.03-7.09(m, 2H), 7.16-7.35(m, 10H)

EXAMPLE 51 preparation of(S)-3-(2-benzofuranylcarbonylamino)-1-furfurylthio-4-phenyl-2-butanone(Compound No. 198 in Table 1)

NMR(CDCl₃, δ): 3.20(s, 2H), 3.21(d, J=5.7 Hz, 2H), 3.66(s, 2H), 5.31(q,J=7.7 Hz, 1H), 6.19(m, 1H), 6.25(m, 1H), 7.18-7.35(m, 8H), 7.40-7.53(m,3H), 7.68(d, J=7.7 Hz, 1H)

EXAMPLE 52 Preparation of(S)-3-(2-chromanylcarbonylamino)-1-furfurylthio-4-phenyl-2-butanone(Compound No. 202 in Table 1)

IR(KBr, cm⁻¹): 3300, 1710, 1650 NMR(CDCl₃, δ): 1.85-2.08(m, 1H),2.20-2.45(m, 1H), 2.52-2.88(m, 2H), 2.95(dd, J=14 Hz, 7.5 Hz, 0.5H),3.05-3.31(m, 3.5H), 3.58(s, 1H), 3.67(s, 1H), 4.51(m, 1H), 5.02(q, J=7.5Hz, 0.5H), 5.11(m, 0.5H), 6.25(d, J=2.0 Hz, 0.5H), 6.26(d, J=1.9 Hz,0.5H), 6.29(m, 0.5H), 6.30(m, 0.5H), 6.80-6.95(m, 2H), 6.99-7.39(m, 9H)

EXAMPLE 53 Preparation of(S)-3-tert-butoxycarbonylamino-1-(3-furylmethylthio)-4-phenyl-2-butanone(Compound No. 204 in Table 1)

IR(KBr, cm⁻¹): 3370, 1705, 1680 NMR(CDCl₃, 67 ): 1.41(s, 9H),2.88-3.22(m, 4H), 3.45(s, 2H), 4.76(dt, J=7.2 Hz, 6.8 Hz, 1H), 5.04(d,J=7.2 Hz, 1H), 6.36(d, J=0.7 Hz, 1H), 7.10-7.42(m, 7H)

EXAMPLE 54 Preparation of(S)-1-furfurylthio-3-(4-oxo-4H-1-benzopyran-2-ylcarbonylamino)-4-phenyl-2-butanone(Compound No. 203 in Table 1)

IR(KBr, cm⁻¹): 3520, 1720, 1650 NMR(CDCl₃, δ): 3.20(s, 2H), 3.21(d,J=7.9 Hz, 2H), 3.67(s, 2H), 5.30(q, J=7.2 Hz, 1H), 6.19(m, 1H), 6.28(m,1H), 7.19-7.37(m, 6H), 7.43-7.53(m, 3H), 7.75(m, 1H), 8.22(dd, J=17 Hz,8 HZ, 1H)

EXAMPLE 55 Preparation of(S)-3-tert-butoxycarbonylamino-4-phenyl-1-(3-thienylmethylthio)-2-butanone(Compound No. 210 in Table 1)

IR(KBr, cm⁻¹): 3378, 1711, 1682 NMR(CDCl₃, δ): 1.41(s, 9H), 2.85-3.20(m, 4H), 3.63(s, 2H), 4.74(m, 1H), 5.05(d, J=7.6 Hz, 1H), 7.01(dd, J=4.9Hz, 1.1 Hz, 1H), 7.05-7.55(m, 7H)

EXAMPLE 56 Preparation of(S)-3-amino-4-phenyl-1-(3-thienylmethylthio)-2-butanone hydrochloride(Compound No. 213 in Table 1)

IR(KBr, cm⁻¹): 3072, 1723, 1599 NMR(CD₃ OD, δ): 3.01(dd, J=14 Hz, 8.4Hz, 1H), 3.13-3.42(m, 3H), 3.75(s, 2H), 4.63(t, J=6.2 Hz, 1H), 7.07(dd,J=5.0 Hz, 1.3 Hz, 1H), 7.18-7.47(m, 7H)

EXAMPLE 57 Preparation of(S)-3-phenoxyacetylamino-4-phenyl-1-(3-thienylmethylthio) -2-butanone(Compound No. 214 in Table 1)

Melting Point: 80°-81° C. IR(KBr, cm⁻¹): 3281, 1732, 1669, 16011NMR(CDCl₃, δ): 2.95-3.20(m, 4H), 3.61(s, 2H), 4.44(d, J=15 Hz, 1H),4.51(d, J=15 Hz, 1H), 5.15(dt, J=7.7 Hz, 6.9 Hz, 1H), 6.88(d, J=8.2 Hz,2H), 6.95-7.40(m, 12H)

EXAMPLE 58 Preparation of(S)-3-(3-methoxyphenoxyacetylamino)-4-phenyl-1-(3-thienylmethylthio)-2-butanone(Compound No. 216 in Table 1)

IR(neat, cm⁻¹): 3407, 1715, 1678, 1603 NMR(CDCl₃, δ): 2.97-3.15(m, 4H),3.61(s, 2H), 3.80(s, 3H), 4.46(s, 2H), 5.14(dt, J=7.8 Hz, 6.8 Hz, 1H),6.40-6.50(m, 2H), 6.53-6.63(m, 1H), 7.01(dd, J=5.0 Hz, 1.3 Hz, 1H),7.05-7.35(m, 9H)

EXAMPLE 59 Preparation of(S)-3-(4-methoxyphenoxyacetylamino)-4-phenyl-1-(3-thienylmethylthio)-2-butanone(Compound No. 217 in Table 1)

Melting Point: 80°-81° C. IR(KBr, cm³¹ 1): 3281, 1726, 1663 NMR(CDCl₃,δ): 2.95-3.17(m, 4H), 3.62(s, 2H), 3.78(s, 3H), 4.39(d, J=15 Hz, 1H),4.45(d, J=15 Hz, 1H), 5.14(dt, J=7.7 Hz, 7.0 Hz, 1H), 6.73-6.88(m, 4H),7.01(dd, J=4.9 Hz, 1.0 Hz, 1H), 7.05-7.38(m, 8H)

EXAMPLE 60 Preparation of(S)-3-(2,4-dimethoxycinnamoylamino)-4-phenyl-1-(3-thienylmethylthio)-2-butanone(Compound No. 219 in Table 1)

Melting Point: 142°-143° C. IR(KBr, cm⁻¹): 3331, 1719, 1647, 1607NMR(CDCl₃, δ): 3.04-3.22(m, 4H), 3.65(s, 2H), 3.84(s, 3H), 3.87(s, 3H),5.19(dd, J=7.0 Hz, 6.4 Hz, 1H), 6.08(d, J=7.0 Hz, 1H), 6.35-6.55(m, 3H),7.02(d, J=4.9 Hz, 1H), 7.07-7.38(m, 7H), 7.39(d, J=8.4 Hz, 1H), 7.89(d,J=16 Hz, 1H)

EXAMPLE 61 Preparation of(S)-3-tert-butoxycarbonylamino-4-phenyl-1-(2-pyridylmethylthio)-2-butanone(Compound No. 226 in Table 1)

NMR(CDCl₃, δ): 1.40(s, 9H), 2.90-3.15(m, 2H), 3.19(d, J=10 Hz, 1H),3.30(d, J=10 Hz, 1H), 3.75(s, 2H), 4.72(dt, J=7.2 Hz, 6.5 Hz, 1H),5.13(d, J=7.2 Hz, 1H), 7.08-7.35(m, 7H), 7.63(td, J=7.6 Hz, 1.9 Hz, 1H),8.54(m, 1H)

EXAMPLE 62

Preparation of(S)-3-tert-butoxycarbonylamino-1-(2-oxazolidinone-4-ylmethylthio)-4-phenyl-2-butanone(Compound No. 223 in Table 1)

NMR(CDCl₃, δ): 1.41(s, 9H), 2.45-2.70(m, 2H), 2.93-3.05(m, 2H)3.05-3.42(m, 2H), 3.90(m, 1H), 4.06(m, 1H), 4.45(m, H), 4.73(m, 1H),5.11(m, 1H), 5.85-6.10(m, 1H), 7.17(d, J=7.9 Hz, 2H), 7.24-7.38(m, 3H)

EXAMPLE 63 Preparation of(S)-3)-tert-butoxycarbonylamino-4-(4-fluorophenyl)-1-furfurylthio-2-butanone(Compound No. 241 in Table 1)

NMR(CDCl₃, δ): 1.41(s, 9H), 2.87-3.14(m, 2H), 3.17(d, J=15 Hz, 1H),3.25(d, J=15 Hz, 1H), 3.65(s, 2H), 4.69(m, 1H), 5.02(d, J=6.2 Hz, 1H),6.19(d, J=3.3 Hz, 1H), 6.29(m, 1H), 6.98(dd, J=7.5 Hz, 6.4 Hz, 2H),7.09(dd, J=23 Hz, 6.4 Hz, 2H), 7.35(m, 1H)

EXAMPLE 64 Preparation of(S)-3-amino-4-(4-fluorophenyl)-1-furfurylthio-2-butanone hydrochloride(Compound No. 243 in Table 1)

IR(KBr, cm⁻¹): 2959, 1718, 1591 NMR(CD₃ OD, δ): 3.0(dd, J=15 Hz, 8.5 Hz,1H), 3.35(dd, J=15 Hz, 8.5 Hz, 1H), 3.36(d, J=15 Hz, 1H), 3.52(d, J=15Hz, 1H), 3.77(s, 2H), 4.62(dd, J=8.3 Hz, 5.7 Hz, 1H), 6.26(d, J=3.2 Hz,1H), 6.34(m, 1H), 7.12(dd, J=8.8 Hz, 7.5 Hz, 2H), 7.33(dd, 7.5 Hz, 5.3Hz, 2H), 7.44(m, 1H)

EXAMPLE 65 Preparation of(S)-3-tert-butoxycarbonylamino-4-(2-chlorphenyl)-1-furfurylthio-2-butanone(Compound No. 247 in Table 1)

NMR(CDCl₃, δ): 1.39(s, 9H), 2.98(dd, J=15 Hz, 8.5 Hz, 1H), 3.30(dd, J=15Hz, 8.5 Hz, 1H), 3.31(s, 2H), 3.69(s, 2H), 4.82(m, 1H), 5.08(d, J=5.8Hz, 1H), 6.21(d, J=3.1 Hz, 1H), 6.29(m, 1H), 7.17-7.23(m, 3H),7.32-7.42(m, 2H)

EXAMPLE 66 Preparation of(S)-3-amino-4-(2-chlorphenyl)-1-furfurylthio-2-butanone hydrochloride(Compound No. 249 in Table 1)

IR(KBr, cm⁻¹): 2835, 1724, 1587 NMR(CD₃ OD, δ): 3.12(dd, J=15 Hz, 8.9Hz, 1H), 3.33(d, J=15 Hz, 1H), 3.42(d, J=15 Hz, 1H), 3.52(dd, J=15 Hz,8.9 Hz, 1H), 3.71(d, J=7.5 Hz, 1H), 3.76(d, J=7.5 Hz, 1H), 4.73(dd,J=8.9 Hz, 6.0 Hz, 1H), 6.25(d, J=2.8 Hz, 1H), 6.37(m, 1H), 7.30-7.41(m,3H), 7.43(m, 1H), 7.51(m, 1H)

EXAMPLE 67 Preparation of(S)-3-tert-butoxycarbonylamino-4-(4-chlorphenyl)-1-furfurylthio-2-butanone(Compound No. 253 in Table 1)

NMR(CDCl₃, δ): 1.41(s, 9H), 2.92(dd, J=14 Hz, 7.2 Hz, 1H), 3.09(dd, J=14Hz, 7.2 Hz, 1H), 3.23(s, 2H), 3.65(s, 2H), 4.71(q, J=7.1 Hz, 1H),5.02(d, J=7.1 Hz, 1H), 6.19(m, 1H), 6.29(m, 1H), 7.07-7.11(m, 2H),7.23-7.29(m, 2H), 7.39(m, 1H)

EXAMPLE 68 Preparation of(S)-4-(4-chlorphenyl)-1-furfurylthio-3-phenoxyacetylamino-2-butanone(Compound No. 256 in Table 1)

NMR(CDCl₃, δ): 3.0(dd, J=14 Hz, 6.5 Hz, 1H), 3.12(dd, J=14 Hz, 6.5 Hz,1H), 3.19(s, 2H), 3.63(s, 2H), 4.48(s, 2H), 5.12(q, J=7.9 Hz, 1H),6.19(m, 1H), 6.29(m, 1H), 6.84-6.89(m, 2H), 7.02-7.10(m, 4H),7.18-7.35(m, 5H)

EXAMPLE 69 Preparation of(S)-3-tert-butoxycarbonylamino-1-furfurylthio-5-phenyl-2-pentanone(Compound No. 273 in Table 1)

NMR(CDCl₃, δ): 1.46(s, 9H), 1.86(m, 1H), 2.19(m, 1H), 2.86(t, J=7.7 Hz,2H), 3.25(d, J=15 Hz, 1H), 3.33(d, J=15 Hz, 1H), 3.73(s, 2H), 4.52(m,1H), 5.14(d, J=7.8 Hz, 1H), 6.20(d, J=2.6 Hz, 1H), 6.28(m, 1H),7.13-7.38(m, 6H)

EXAMPLE 70 Preparation of(S)-1-furfurylthio-3-phenoxyacetylamino-5-phenyl-2-pentanone (CompoundNo. 277 in Table 1)

IR(neat, cm⁻¹): 3420, 3320, 1710, 1670 NMR(CDCl₃, δ): 1.94(m, 1H),2.29(m, 1H), 2.60(m, 2H), 3.27(s, 2H), 3.71(s, 2H), 4.52(s, 2H), 4.96(m,1H), 6.19(m, 1H), 1H), 6.28(m, 1H), 6.93-7.38(m, 12H)

EXAMPLE 71 Preparation of(S)-3-tert-butoxycarbonylamino-1-furfurylthio-4-(1-naphthyl)-2-butanone(Compound No. 282 in Table 1)

NMR(CDCl₃, δ): 1.40(s, 9H), 2.99(s, 2H), 3.49(d, J=7.5 Hz, 2H), 3.59(s,2H), 4.87(q, J=7.5 Hz, 1H), 5.11(d, J=7.5 Hz, 1H), 6.13(m, 1H), 6.26(m,1H), 7.26-7.42(m, 4H), 7.49-7.62(m, 2H), 7.77(d, J=7.9 Hz, 1H), 7.87(d,J=7.5 Hz, 1H), 8.15(d, J=7.2 Hz, 1H)

EXAMPLE 72 Preparation of(S)-1-furfurylthio-4-(1-naphthyl)-3-phenoxyacetylamino-2-butanone(Compound No. 286 in Table 1)

NMR(CDCl₃, δ): 2.89(d, J=15 Hz, 1H), 3.01(d, J=15 Hz, 1H), 3.54(m, 2H),3.57(s, 2H), 4.39(d, J=15 Hz, 1H), 4.47(d, J=15 Hz, 1H), 5.25(q, J=7.4Hz, 1H), 6.11(m, 1H), 6.24(m, 1H), 6.83(d, J=7.5 Hz, 2H), 7.02(t, J=7.5Hz, 1H), 7.18-7.39(m, 6H), 7.50-7.62(m, 2H), 7.77(d, J=8.2 Hz, 1H),7.87(d, J=7.5 Hz, 1H), 8.23(d, J=8.2 Hz, 1H)

EXAMPLE 73 Preparation of(S)-3-tert-butoxycarbonylamino-1-furfurylthio-4-(2-naphthyl)-2-butanone(Compound No. 290 in Table 1)

NMR(CDCl₃, δ): 1.39(s, 9H), 3.05-3.35(m, 4H), 3.63(s, 2H), 4.82(m, 1H),5.09(d, J=6.8 Hz, 1H), 6.13(d, J=2.9 Hz, 1H), 6.26(m, 1H), 7.28-7.35(m,2H), 7.42-7.52(m, 2H), 7.61(s, 1H), 7.70-7.85(m, 3H) J=8.2 Hz, 1H)

EXAMPLE 74 Preparation of(S)-1-furfurylthio-3-isobutoxycarbonylamino-4-(2-naphthyl)-2-butanone(Compound No. 291 in Table 1)

Melting Point: 84°-87° C. IR(KBr, cm⁻¹): 3330 1735, 1685 NMR(CDCl₃, δ):0.88(d, J=6.7 Hz, 6H), 1.86(m, 1H), 3.16-3.35(m, 2H), 3.19(s, 2H),3.62(s, 2H), 3.82(d, J=6.7 Hz, 2H), 4.91(q, J=7.5 Hz, 1H), 5.25(d, J=7.5Hz, 1H), 6.13(m, 1H), 6.25(m, 1H), 7.24-7.34(m, 2H), 7.42-7.50(m, 2H),7.61(s, 1H), 7.75-7.85(m, 3H)

EXAMPLE 75 Preparation of(S)-3-tert-butoxycarbonylamino-1-furfuryloxy-2-heptanone (Compound No.298 in Table 1)

IR(KBr, cm⁻¹): 3349, 1709 NMR(CDCl₃, δ): 0.87(t, J=6.8 Hz, 3H),1.13-1.37(m, 4H), 1.43(s, 9H), 1.45(m, 1H), 1.79(m, 1H), 4.17(d, J=18Hz, 1H), 4.25(d, J=18 Hz, 1H), 4.46(m, 1H), 4.52(d, J=13 Hz, 1H),4.58(d, J=13 Hz, 1H), 5.10(d, J=7.9 Hz, 1H), 6.30-6.39(m, 2H), 7.42(m,1H)

EXAMPLE 76 Preparation of(S)-3-tert-butoxycarbonylamino-1-(3-thienylmethoxy)-2-heptanone(Compound No. 304 in Table 1)

IR(KBr, cm⁻¹): 3349, 1709 NMR(CDCl₃, δ): 0.88(t, J=6.9 Hz, 3H),1.12-1.39(m, 4H), 1.43(s, 9H), 1.47(m, 1H), 1.79(m, 1H), 4.15(d, J=15Hz, 1H), 4.23(d, J=15 Hz, 1H), 4.49(m, 1H), 4.57(d, J=12 Hz, 1H),4.64(d, J=12 Hz, 1H), 5.11(d, J=7.8 Hz, 1H), 7.09(m, 1H), 7.25(m, 1H),7.31(m, 1H)

EXAMPLE 77 Preparation of (S)-3-amino1-(3-thienylmethoxy)-2-heptanonehydrochloride (Compound No. 306 in Table 1)

IR(KBr, cm⁻¹): 3441, 1732, 1587 NMR(CD3OD, δ): 0.93(t, J=6.9 Hz, 3H),1.17-1.59(m, 4H), 1.77(m, 1H), 1.98(m, 1H), 4.27(d, J=15 Hz, 1H),4.34(d, J=15 Hz, 1H), 4.35(m, 1H), 4.60(d, J=15 Hz, 1H), 4.66(d, J=15Hz, 1H), 7.12(m, 1H), 7.37-7.51(m, 2H)

EXAMPLE 78 Preparation of(S)-3-tert-butoxycarbonylamino-1-furfuryloxy-4-phenyl-2-butanone(Compound No. 316 in Table 1)

NMR(CDCl₃, δ): 1.39(s, 9H), 2.83-3.14(m, 2H), 3.94(d, J=16 Hz, 1H),4.18(d, J=16 Hz, 1H), 4.38-4.73(m, 3H), 5.11(m, 1H), 6.27(d, J=2.7 Hz,1H), 6.32(m, 1H), 7.05-7.40(m, 6H)

EXAMPLE 79 Preparation of(S)-3-tert-butoxycarbonylamino-1-(N-furfuryl-N-methylamino)-4-phenyl-2-butanone(Compound No. 377 in Table 1)

NMR(CDCl₃, δ): 1.40(s, 9H), 2.27(s, 3H), 2.85-3.08(m, 2H), 3.07(d, J=18Hz, 1H), 3.36(d, J=18 Hz, 1H), 3.55(d, J=14 Hz, 1H), 3.65(d, J=14 Hz,1H), 4.67(q, J=7.2 Hz, 1H), 5.13(d, J=7.2 Hz, 1H), 6.17(d, J=3.0 Hz,1H), 6.31(m, 1H), 7.07-7.40(m, 6H)

EXAMPLE 80 Preparation of(S)-3-tert-butoxycarbonylamino-1-furfurylthio-4-(2-thienyl)-2-butanone(Compound No. 436 in Table 1)

NMR(CDCl₃, δ): 1.44(s, 9H), 3.15-3.42(m, 4H), 3.68(s, 2H), 4.71(dt,J=7.1 Hz, 6.5 Hz, 1H), 5.11(d, J=7.1 Hz, 1H), 6.19(d, J=2.9 Hz, 1H),6.29(m, 1H), 6.82(d, J=3.1 Hz, 1H), 6.93(m, 1H), 7.18(d, J=5.8 Hz, 1H),7.36(m, 1H)

TEST EXAMPLE Measurement of Inhibitory Activity against Thiol Protease

Through the known method disclosed in Journal of Biological Chemistry,vol. 259, page 3210, 1984, m-calpain was purified from a brain of rat.The inhibitory activity against it was measured and determined accordingto the method disclosed in Journal of Biological Chemistry, vol. 259,page 12489, 1984. The results are set forth in Table 2 below, indicatingthat the compounds according to the present invention exhibit stronginhibitory activity against thiol protease.

                  TABLE 2                                                         ______________________________________                                        Example No.                                                                   (Compound No. in Table 1)                                                                         IC.sub.50 (μm)                                         ______________________________________                                        17 (No. 86)         12.2                                                      18 (No. 87)         13.0                                                      38 (No. 171)        17.0                                                      58 (No. 216)        4.5                                                       60 (No. 219)        14.5                                                      ______________________________________                                    

What we claim is:
 1. An aminoketone derivative of the following formulaor a pharmaceutically acceptable salt thereof: ##STR331## wherein, R¹ ishydrogen ##STR332## wherein R⁵ is a member selected from the groupconsisting of (a) C₁ to C₂₀ alkyl which is unsubstituted or issubstituted by at least one substituent selected from the groupconsisting of (1) C₆ to C₁₄ aryl, (2) fluorenyl, (3) a C₃ to C₉heterocyclic group containing a hetero atom selected from the group ofnitrogen, sulfur and oxygen, which group may be substituted by C₆ to C₁₀arylamino or oxo, (4) C₃ to C₁₅ cycloalkyl, (5) C₃ to C₁₅ cycloalkyloxy,(6) C₆ to C₁₄ aryloxy which may be substituted by C_(l) to C₃ alkoxy,halogen, C₁ to C₃ alkyl or trifluoromethyl, (7) C₇ to C₂₀ aralkyloxy,(8) C₆ to C₁₄ arylthio, (9) hydroxyl and (10) C₂ to C₁₀ alkanoyloxy,(b)C₂ to C₁₀ alkenyl which is unsubstituted or is substituted by (1) C₆ toC₁₀ aryl which may be substituted by C₁ to C₃ alkoxy, or (2) thiazolylwhich may be substituted by C₂ to C₅ alkanoylamino, (c) C₆ to C₁₄ arylwhich is unsubstituted or is substituted by C₆ to C₁₀ aryloxy, and (d) a5 or 6 membered heterocyclic group containing at least one hetero atomselected from the group consisting of nitrogen, sulfur and oxygen, whichheterocyclic group is unsubstituted or is substituted by oxo, R² and R⁴are independently hydrogen or C₁ to C₅ alkyl, R³ is (a) hydrogen, or (b)C₁ to C₂₀ alkyl which is unsubstituted or is substituted by (1) C₂ to C₄alkoxycarbonyl, (2) C₃ to C₁₀ cycloalkyl, (3) C₆ to C₁₄ aryl which maybe substituted by halogen or thienyl, or R³ when taken together with R⁴,forms C₁ to C₁₀ alkylene, A is oxygen, sulfur or ##STR333## wherein R⁶is hydrogen or C₁ to C₅ alkyl, n is an integer of 1 to 10, and X is a 5to 6 membered heterocyclic group containing at least one hetero atomselected from the group consisting of nitrogen, sulfur and oxygen whichheterocyclic group is unsubstituted or is substituted by oxo.
 2. Acompound according to claim 1 whereinR¹ is hydrogen, ##STR334## whereinR⁵ is a member selected from the group consisting of (a) C₁ to C₁₀ alkylwhich is unsubstituted or is substituted by at least one substituentselected from the group consisting of (1)C₆ to C₁₄ aryl, (2) fluorenyl,(3) thiazolyl which may be substituted by phenylamino, (4) benzofuranyl,(5) chromanyl, (6) 4-oxochromenyl, (7) C₃ to C₁₀ cycloalkyloxy, (8) C₆to C₁₄ aryloxy which may be substituted by C₁ to C₃ alkoxy, halogen, C₁to C₃ alkyl or trifluoromethyl, (9) C₇ to C₁₅ aralkyloxy, (10) C₆ to C₁₀arylthio and (11) C₂ to C₆ alkanoyloxy, (b) C₂ to C₆ alkenyl which isunsubstituted or is substituted by (1) C₆ to C₁₀ aryl which may besubstituted by C₁ to C₃ alkoxy or (2) thiazolyl which may be substitutedby C₂ to C₅ alkanoylamino, (c) C₆ to C₁₀ aryl which is unsubstituted oris substituted by C₆ to C₁₀ aryloxy, and (d) pyrrolidinyl which may besubstituted by oxo, and X is (1) furyl, (2) thienyl, (3) oxazolidinylwhich may be substituted by oxo or (4) pyridinyl.
 3. A compoundaccording to claim 1 wherein R¹ is ##STR335## wherein R⁵ is a memberselected from the group consisting of (a) C₁ to C₅ alkyl which isunsubstituted or is substituted by C₆ to C₁₀ aryloxy which may besubstituted by C₁ to C₃ alkoxy, and(b) C₂ to C₅ alkenyl which isunsubstituted or is substituted by C₆ to C₁₀ aryl which may besubstituted by C₁ to C₃ alkoxyl, R² and R⁴ are hydrogen, R³ is C₁ to C₁₀alkyl which is unsubstituted or is substituted by C₆ to C₁₀ aryl, A issulfur, n is an inter of 1 to 3, and X is furyl or thienyl.
 4. Apharmaceutical composition for treating diseases resulting from abnormalsthenia of thiol protease which comprises an effective amount of acompound or salt thereof as defined in claim 1 and a pharmaceuticallyacceptable carrier therefor.
 5. A method for the treatment of a diseaseresulting from abnormal sthenia of thiol protease which comprisesadministering to a patient in need of such treatment an effective amountof a compound or a salt thereof as defined in claim 1.